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Sirt6 attenuates chondrocyte senescence and osteoarthritis progression

ABSTRACT: Sirt6 attenuates chondrocyte senescence and osteoarthritis progression

PROVIDER: PRJNA851254 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19760771_1.fastq.gz	Fastqsanger.gz
	SRR19760771_2.fastq.gz	Fastqsanger.gz
	SRR19760772_1.fastq.gz	Fastqsanger.gz
	SRR19760772_2.fastq.gz	Fastqsanger.gz
	SRR19760773_1.fastq.gz	Fastqsanger.gz

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Sirt6 attenuates chondrocyte senescence and osteoarthritis progression

Project description:Sirt6 attenuates chondrocyte senescence and osteoarthritis progression

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Sirt6 attenuates chondrocyte senescence and osteoarthritis progression.

Project description:Sirt6 has been implicated as a key regulator in aging-related diseases, including osteoarthritis. However, its functional role and molecular mechanism in chondrocyte senescence and osteoarthritis pathophysiology remain largely undefined. Here we show that Sirt6 deficiency exaggerates chondrocyte senescence and osteoarthritis progression, whereas intra-articular injection of adenovirus-Sirt6 markedly attenuates surgical destabilization of medial meniscus-induced osteoarthritis. Mechanistically, Sirt6 can directly interact with STAT5 and deacetylate STAT5, thus inhibiting the IL-15/JAK3-induced STAT5 translocation from cytoplasm to nucleus, which inactivates IL-15/JAK3/STAT5 signaling. Mass spectrometry revealed that Sirt6 deacetylated conserved lysine 163 on STAT5. Mutation of lysine 163 to arginine in STAT5 abolished the regulatory effect of Sirt6. In vivo, specific ablation of Sirt6 in chondrocytes exacerbated osteoarthritis. Pharmacological activation of Sirt6 substantially alleviated chondrocyte senescence. Taken together, Sirt6 attenuates chondrocyte senescence by inhibiting IL-15/JAK3/STAT5 signaling. Targeting Sirt6 represents a promising new approach for osteoarthritis.

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Matrix stiffening promotes chondrocyte senescence and the osteoarthritis development through downregulating HDAC3

Project description:Cartilage aging is a quintessential feature of knee osteoarthritis, and extracellular matrix (ECM) stiffening is a typical feature of cartilage aging. However, the mechanism of ECM stiffening to influence chondrocytes and downstream molecules is still poorly understood. Here, we mimicked the physiological and pathological stiffness of human cartilage by using polydimethylsiloxane-based substrates. We show that the epigenetic regulation of Parkin by histone deacetylase 3 (HDAC3) represents a new mechanosensitive mechanism by which the stiff matrix affects the physiology of chondrocytes. We found that ECM stiffening could accelerate the senescence of cultured chondrocytes in vitro, and also found that stiff ECM downregulated HDAC3, drove Parkin acetylation to activate excessive mitophagy, and accelerated chondrocyte senescence and osteoarthritis in mice. In contrast, intra-articular injection of adeno-associated virus expressing HDAC3 restored the young phenotype of aged chondrocytes stimulated by ECM stiffening and alleviated osteoarthritis in mice. Our findings indicate that changes in the mechanical properties of ECM initiate pathogenic mechanotransduction signals, promote the acetylation of Parkin and hyperactivate mitophagy, and damage the health of chondrocytes. These findings may provide new insights into how the mechanical properties of ECM regulate chondrocytes.

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Dynamic chromatin accessibility tuning of long noncoding RNA ELDR accelerates chondrocyte senescence and osteoarthritis

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The gene expression profiling among normal chondrocyte, osteoarthritis chondrocyte and chondrosarcoma

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MYL3 protects chondrocytes from senescence by inhibiting clathrin-mediated endocytosis and activating of Notch signaling

Project description:As the unique cell type in articular cartilage, chondrocyte senescence is a crucial cellular event contributing to osteoarthritis development. Here we show that clathrin-mediated endocytosis and activation of Notch signaling promotes chondrocyte senescence and osteoarthritis development, which is negatively regulated by myosin light chain 3. Myosin light chain 3 (MYL3) protein levels decline sharply in senescent chondrocytes of cartilages from model mice and osteoarthritis (OA) patients. Conditional deletion of Myl3 in chondrocytes significantly promoted, whereas intra-articular injection of adeno-associated virus overexpressing MYL3 delayed, OA progression in male mice. MYL3 deficiency led to enhanced clathrin-mediated endocytosis by promoting the interaction between myosin VI and clathrin, further inducing the internalization of Notch and resulting in activation of Notch signaling in chondrocytes. Pharmacologic blockade of clathrin-mediated endocytosis-Notch signaling prevented MYL3 loss-induced chondrocyte senescence and alleviated OA progression in mice. Our results establish a previously unknown mechanism essential for cellular senescence and provide a potential therapeutic direction for OA.

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Project description:Osteoarthritis (OA) is a widespread age-related joint disease caused by the gradual loss of chondrocyte function along with age. Here, we found that UFMylation modification was lower-leveled in senescent cartilage, mediated chondrocyte senescence and OA phenotypes through targeting CAVIN1, which acted as a stimulator in chondrocyte senescence, mainly through promoting CPT1 expression and activating fatty acid β-oxidation (FAO). Physiologically, FAO was at a very low level in chondrocytes, while the anomalous activation of FAO accelerated chondrocyte senescence. UFMylation of CAVIN1 promoted its binding with TRIP12, leading to ubiquitination degradation. Therefore, UFMylation played a pivotal role in post-translationally modification of CAVIN1. Polymeric micellar nanoparticles (NPs) conjugated with UFM1 improved the stability of UFM1 recombinant protein (UFM1-rp), and extended the retention time of UFM1-rp in the mouse joint cavity. The administration of UFM1 into mouse joints using an advanced NP delivery system is effective in attenuating age-related pathogenesis. Therefore, we uncovered a previously unknown mechanism, UFM1-CAVIN1-CPT1 axis, in the protection of OA progression and constructed a new drug for OA treatment, and have provided important preliminary evidence toward the translation of our findings into clinical usage.

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Silencing of pericentric heterochromatin associated with SIRT6-dependent H3K18 deacetylation protects against mitotic errors and cellular senescence

Project description:Pericentric heterochromatin silencing at mammalian centromeres is essential for mitotic fidelity and genomic stability. Defective pericentric silencing is observed in senescent cells, aging tissues, and mammalian tumors, but the underlying mechanisms and functional consequences of these defects are unclear. Here, we uncover a pivotal role of the human SIRT6 enzyme in pericentric transcriptional silencing, and this function protects against mitotic defects, genomic instability, and cellular senescence. At pericentric heterochromatin, SIRT6 promotes deacetylation of a new substrate, histone H3 lysine K18 (H3K18), and inactivation of SIRT6 in cells leads to H3K18 hyperacetylation and aberrant accumulation of pericentric transcripts. Strikingly, RNAi-depletion of these transcripts rescues the mitotic and senescence phenotypes of SIRT6-deficient cells. Together, our findings reveal a new function for SIRT6 and H3K18Ac regulation at heterochromatin, and demonstrate the pathogenic role of de-regulated pericentric transcription in aging- and cancer- related cellular dysfunction. H3K18ac, H3K9ac, H3K9me3, H3K56ac and Input ChIP-seq for U2OS cell

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